The long term objective of this proposal is to identify and characterize the T cells responsible for causing autoimmune type I diabetes. By identifying the specific populations involved, more precise intervention approaches can be employed to prevent the development of the disease. As has been determined to be a central theme of all projects in this proposal, we have identified a link between apoptosis and autoimmune disease. Specifically, we conclude from our studies of diabetes prone BB- DP rats that the autoreactive T cells are resistant to apoptosis and anergy induction and they are best characterized as medullary thymocytes rather than mature peripheral T cells. Our working hypothesis is that the resistant phenotype is associated with the way in which these thymocytes escape the normal selection process that deletes self reactive T cells in the thymus. This resistance to anergy and apoptosis is a critical characteristic of an autoreactive "medullary thymocyte" subset involved in the development of autoimmune diabetes. The specific aims of this proposal will focus on the genetic contribution of diabetes susceptibility genes to the characteristics ascribed to the autoreactive T cells and determining if the autoreactive T cells can be isolated from the thymus of diabetes prone and non diabetic animals.